Open AccessAcute Neurotoxicity of Antisense Oligonucleotides After Intracerebroventricular Injection Into Mouse Brain Can Be Predicted from Sequence Features
Author(s) -
Peter Hagedorn,
Jeffrey M. Brown,
Amy Easton,
Maria Pierdomenico,
Kelli Jones,
R. E. Olson,
Stephen E. Mercer,
Dong Li,
James Loy,
Anja Høg,
Marianne L. Jensen,
Martin R. Gill,
Angela Cacace
Publication year - 2022
Publication title -
nucleic acid therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.255
H-Index - 67
eISSN - 2159-3345
pISSN - 2159-3337
DOI - 10.1089/nat.2021.0071
Subject(s) - oligonucleotide , neurotoxicity , sequence (biology) , in vivo , dosing , pharmacology , computational biology , drug discovery , medicine , biology , neuroscience , bioinformatics , toxicology , toxicity , biochemistry , gene , genetics
Antisense oligonucleotides are a relatively new therapeutic modality and safety evaluation is still a developing area of research. We have observed that some oligonucleotides can produce acute, nonhybridization dependent, neurobehavioral side effects after intracerebroventricular (ICV) dosing in mice. In this study, we use a combination of in vitro , in vivo , and bioinformatics approaches to identify a sequence design algorithm, which can reduce the number of acutely toxic molecules synthesized and tested in mice. We find a cellular assay measuring spontaneous calcium oscillations in neuronal cells can predict the behavioral side effects after ICV dosing, and may provide a mechanistic explanation for these observations. We identify sequence features that are overrepresented or underrepresented among oligonucleotides causing these reductions in calcium oscillations. A weighted linear combination of the five most informative sequence features predicts the outcome of ICV dosing with >80% accuracy. From this, we develop a bioinformatics tool that allows oligonucleotide designs with acceptable acute neurotoxic potential to be identified, thereby reducing the number of toxic molecules entering drug discovery pipelines. The informative sequence features we identified also suggest areas in which to focus future medicinal chemistry efforts.